表柔比星膀胱内灌注化疗方案的优化课件

表柔比星膀胱内灌注方案的优化福建省立医院泌尿外科李涛Thereisnosingledrugthatissuperiorwithregardstoefficacy.MitomycinC,epirubicinanddoxorubicinhaveallshownabeneficialeffect(evidence:1b).2010EAU对NMIBC的治疗的推荐TURBT+即刻单次膀胱内灌注复发复发/进展根治性膀胱切除术化疗BCG+维持治疗单瘤、原发低分级Ta多发、复发低分级肿瘤任何T1和/或G3和/或原位癌观察复发/进展BCG+维持治疗低危中危高危TURBT+单次化疗TURBT+单次化疗表柔比星膀胱内灌注方案的优化提高疗效（尤其是能否替代BCG？）减少不良反应增加便利性（减少不必要的灌注次数）表柔比星膀胱内灌注方案的优化剂量优化灌注频率和疗程的优化联合用药剂型优化比较法玛新不同剂量膀胱内灌注给药的研究

[50mg/50ml,80mg/50ml]Ali-El-DeinB,etal.TheJournalofUrology1997;158:68-74.膀胱内灌注在术后7-14天开始，每周进行一次，进行8周然后每月进行一次至一年疗程结束随访时间为12月-48月(平均为30.1月)组1：法玛新50mg/50ml生理盐水组2：法玛新80mg/50ml生理盐水组3：阿霉素50mg/50ml生理盐水组4：未接受任何辅助治疗浅表性膀胱癌患者R手术基线特征组1组2组3组4合计(%)分级pT1/pTa/Tis57/7/456/12/856/4/-55/6/-88.6/11.4/4.7分期I/II/III6/50/811/47/1010/42/812/40/915.4/70.8/13.8DNA双/四/异倍体48/8/850/14/440/12/845/13/372.3/18.6/19.1发病数单发/多发22/4228/4019/4119/4234.8/65.2肿瘤大小<3cm/3cm36/2846/2242/1845/1666.8/33.2Ali-El-DeinB,etal.TheJournalofUrology1997;158:68-74.研究结果：复发率Ali-El-DeinB,etal.TheJournalofUrology1997;158:68-74.平均随访30.1个月复发患者(%)(n=64)(n=68)(n=60)(n=61)组1-3vs.组4 p=0.0002组1-2vs.组3 p=0.02组1-2 p>0.05研究结果：不良反应Ali-El-DeinB,etal.TheJournalofUrology1997;158:68-74.法玛新50mg组(n=64)不良反应发生例数(个)研究结论：法玛新的剂量和疗效正相关临床推荐TURBT术后可常规使用50mg法玛新，最高可以用到80mg法玛新局部刺激性小，严重不良反应少比较Ta/T1期移行细胞膀胱癌患者

接受TURBT术后两次法玛新膀胱内灌注研究SaikaT,etal.WorldJUrol2010.主要终点：至首次复发时间N=303A.TURBT+法玛新

20mg/40ml(N=79)TURBT术后1小时内即刻灌注1次，第二天早晨灌注1次，术后24小时内灌注2次C.仅TURBT(N=77)Ta/T1

移行细胞癌NMIBC患者B.TURBT+法玛新50mg/100ml

(N=84)TURBT术后1小时内即刻灌注1次，第二天早晨灌注1次，术后24小时内灌注2次R中位随访44个月基线特征ABC总计中位年龄(岁)69697169性别(男性/女性)67/1680/1074/10221/36原发/复发50/3351/3950/34151/106单瘤/多瘤38/4538/5236/48112/145原发单瘤/原发多瘤28/2228/2324/2680/71复发单瘤/复发多瘤10/2310/2912/2232/74最大肿瘤直径<1cm49%56%48%51%肿瘤分级(G1/G2/G3)21/49/1230/42/1826/44/1477/135/44肿瘤分期(Ta/T1)45/3654/3654/30153/102总计839084257SaikaT,etal.WorldJUrol2010.研究结果：无复发生存SaikaT,etal.WorldJUrol2010.ABC中位RFS(月)243813时间(年)generalizedWilcoxontesBvs.C,P=0.041008060402000.01.02.03.04.05.0A法玛新20mg无复发率(%)B法玛新50mgC无法玛新研究结果：不良事件研究结论：TURBT后24小时内给予膀胱内灌注两次法玛新50mg比两次灌注20mg可进一步延长复发时间，且副作用很小。法玛新20法玛新50P1级膀胱刺激性(%)22.935.60.1061级外周红细胞减少(n)22-1级血清转氨酶升高(n)13-1级外周白细胞减少－1-所有不良反应均可逆SaikaT,etal.WorldJUrol2010.比较高剂量法玛新膀胱内灌注与BCG

对中危浅表性膀胱癌患者预防作用的研究MoutzourisG,etal.EurUrolSuppl2007;6(2):171,Abstract595.DFS复发安全性N=234法玛新80mg/50ml生理盐水(N=121)BCG(N=113)TURBT术后原发或复发TaG2-3,T1G1-2TCC患者R每周膀胱内灌注，共六周；后续第3/6/12/18/24/30/36个月给予3次每周膀胱内灌注中位随访21个月前瞻性随机对照研究研究结果研究结论高剂量膀胱内灌注法玛新作为延长治疗方案耐受性良好对于中危NMIBC患者TURBT术后复发的预防疗效与BCG相同可评估患者法玛新(N=109)BCG(N=103)P肿瘤复发(%)31.220.40.1016中位DFS(月)23.2423.260.0778化学性膀胱炎(G1-G3)，%47.9354.870.1213因膀胱炎停药，%5.799.73-MoutzourisG,etal.EurUrolSuppl2007;6(2):171,Abstract595.表柔比星膀胱内灌注方案的优化剂量优化灌注频率和疗程的优化联合用药剂型优化HendricksenK,WitjesWP,IdemaJG,etal.EurUrol，2008，53(5)：984-991.Patientswithintermediate-andhigh-riskurothelialcellcarcinomaofthebladder,exceptcarcinomainsitu,wererandomisedforadjuvantintravesicalinstillationswith50mgepirubicin/50mlNaClfor1h.Group1received4weeklyand5monthlyinstillations(standardschedule).group2receivedthesamescheduleasgroup1,butwithanadditionalinstillation<48hafterTURBT.group3receivedthesameschemeasgroup1,butwithadditionalinstillationsat9and12mo(maintenanceschedule).group1group2group35-yrrecurrencefree44.4%42.7%45.0%5-yrprogressionfree90.0%87.7%88.2%TürkeriL,TanıdırY,ÇalÇ,etal.

UrolInt,2010,85(3):261-5.Comparisonoftheefficacyofsingleordoubleintravesicalepirubicininstillationintheearlypostoperativeperiodtopreventrecurrencesinnon-muscle-invasiveurothelialcarcinomaofthebladder:prospective,randomizedmulticenterstudy.primaryandsolitaryormultiple(3orless)Ta(grade2-3)orT1(grade1-2)tumorswereenrolled.Atotalof299patientsfrom24institutionswererandomizedtoreceiveeitherasingledoseof100mgepirubicininstillationwithin6horasecond100mgepirubicininstillationduringthe12th-18thhoursafteracompleteTUR-BT.RESULTS:Thefollow-upanddisease-freesurvivalperiodswere16.9monthsand16months,respectively.CONCLUSIONS:Asecondintravesicalepirubicininstillationdidnotprovideanysignificantbenefit.比较Ta/T1膀胱癌TUR术后

长疗程与短疗程法玛新膀胱内灌注的研究KogaH,etal.JUrol2004;171(1):153-157.N=150复发率安全性1年：法玛新30mg/30ml生理盐水×19(N=77)3个月：法玛新30mg/30ml生理盐水×9(N=73)TUR术后Ta/T1膀胱癌患者R膀胱内灌注次数1年组3个月组1TUR后<24小时2TUR后2-3天3TUR后1周4TUR后2周>55－10：每2周5－9：每2周11－19：每月－1年组3个月组5年RFS(％)85.263.9KogaH,etal.JUrol2004;171(1):153-157.研究结果：复发率术后时间(月)P=0.005无肿瘤复发患者比例(%)10080604020001224364860721年组3个月组研究结果：不良反应研究结论：与短疗程法玛新膀胱内灌注相比，长疗程（1年）法玛新明显降低复发率，且不增加严重不良反应。KogaH,etal.JUrol2004;171(1):153-157.严重局部不良反应发生率P=NS表柔比星膀胱内灌注方案的优化剂量优化灌注频率和疗程的优化联合用药剂型优化RaitanenMP,LukkarinenO,FinnishMulticentreStudyGroup.

BrJUrol,1995,76(6):697-701.

Acontrolledstudyofintravesicalepirubicinwithorwithoutalpha2b-interferonasprophylaxisforrecurrentsuperficialtransitionalcellcarcinomaofthebladder.FinnishMulticentreStudyGroup.PATIENTSANDMETHODS:81patientswithsuperficial(stageTaandT1),wellormoderatelydifferentiated(grades1and2)TCCwererandomizedintothreegroups:Group1：TURalone;Group2：50mgepirubicin;Group3：50mgepirubicincombinedwith10MUalpha2b-IFN,intravesically.Theinstillationswerestarted1weekafterTURandwereperformedweeklyduringthefirstmonthandthenonceamonthforoneyear.RESULTS:Thepatientswerefollowedforameanof20months.Patientsreceivingintravesicalchemoimmunotherapy(Group3)hadthemostfavourableoutcome;theyhadcomparativelylowerrecurrenceandtumourrates,fewerpatientswithrecurrencesand,mostimportantly,thelongestdisease-freeinterval.Side-effectsweremostlymildandtransient,andnodifferenceswerefoundamongthegroups.MalmstromP,WiklundF,DuchekM.etal.

JournalofUrology,2008,179(4-sup1):587

ADJUVANTINTRAVESICALEPIRUBICINANDINTERFERON2bISCOMPARABLETOBCGFORTREATMENTOFT1TUMOURSOFTHEURINARYBLADDERBCGEpirubicin+Interferonα2bN(T1bladdercancer)117118Recurrence25%23%progression11%9%Worsenedurinarysymptomsat6monthsfollow-up24%16%ThefirstTURoftheT1tumourwasfollowedwithin4-6weeksbyasecond-lookresectionincludingbladdermappingandresectionbiopsyoftheprostaticurethra.TwoweekslaterpatientsreceivedaccordingtorandomisationscheduleeitherBCG(Oncotice)orthecombinationofepirubicin(Farmorubicin50mg）andInterferonα2b(100,000IU)Bothregimensgivenasinductiontreatmentfor6weeksfollowedbymaintenancetherapyfor2years.Themeandurationoffollow-upispresently3.2(0.1-7.9)years.NaitoS,etal.TheJournalofUrology，2008，179:485-490.LC：干酪乳酸菌多中心、前瞻性、随机对照研究临床诊断为浅表性膀胱癌患者TUR术后1周内膀胱内灌注(法玛新30mg/30ml生理盐水)共2次R法玛新组(N=102)术后3月内附加6次法玛新膀胱内灌注法玛新联合LC组(N=100)术后3月内附加6次法玛新膀胱内灌注口服干酪乳杆菌3mg/天持续1年评估复发、疾病进展、预后及药物不良反应基线特征NaitoS,etal.TheJournalofUrology2008;179:485-490.单药组联合组P总计1021000.2510性别(男/女)86/1678/22年龄

<70岁55530.8955≥70岁4747吸烟(是/否)53/4955/450.6650肿瘤类型原发单瘤40400.9903原发多瘤5250复发单瘤1010T分类(Ta/T1)53/4952/480.9955肿瘤分级(1/2)21/8121/790.9425肿瘤大小<1cm/≥1cm33/6931/690.8363研究结果：复发率单药组联合组中位随访(月)26.943.6复发率(%)41.226.03年RFS(%)59.974.6P=0.0234NaitoS,etal.TheJournalofUrology2008;179:485-490.100806040200012243648607284手术后时间(月)无复发生存率(%)单药组联合组研究结果：不良反应研究结论：浅表性膀胱癌TUR术后膀胱内灌注法玛新联合口服干酪乳杆菌是预防复发的一种新的治疗方法。NaitoS,etal.TheJournalofUrology2008;179:485-490.毒性单药组(%)联合组(%)P(χ2测试)排尿疼痛

1级/2级33.3/7.824.0/7.00.929尿频

1级/2级21.6/8.819.0/6.00.905肉眼血尿

1级/2级14.7/4.014.0/2.00.836便秘

1级/2级2.0/2.04.0/2.00.895腹泻

1级/2级0/01.0/1.01.000GurtowskaN,KloskowskiT,DrewaT.

MedSciMonit,2010,16(10):218-223.

CiprofloxacincriteriainantimicrobialprophylaxisandbladdercancerrecurrenceAmongfluoroquinolones,ciprofloxacinisdistinguishedbystronginhibitionoftopoisomeraseII.Antiproliferativepotentialoftheciprofloxacinagainsthumanbladdercellsvariesaccordingtodrugconcentrationandtimeofincubation.LowurinepHcanenhancetheantitumoreffectofciprofloxacin.Ciprofloxacinenhancestheeffectofactionofdoxorubicinandepirubicin,whichareusedtopreventbladdercancerrecurrenceaftertransurethralresectionofsuperficialbladdercancer.Wethink